The present application is directed to peptides which can stimulate cell survival and proliferation, pharmaceutical and cosmetic compositions thereof, and methods for their use. More specifically, the peptides are active to stimulate the survival and proliferation of fibroblasts and/or endothelial cells.
The ability of organisms to repair or regenerate tissues is one of the most important features in nature and is a survival factor for life forms from bacteria to humans. The skin, the largest organ in humans, exhibits a complex mechanism of wound healing and regeneration. While “regeneration” describes the tissue-specific replacement of tissue such as superficial epidermis, mucosa or skin in response to natural fluctuation or damage, “repair”, or wound healing, refers to non-specific healing of wounds involving scar formation and fibrosis.
In mature skin, wound repair usually begins with hemostatic and inflammatory processes, followed by a proliferative phase and epithelialization, angiogenesis and collagen production, and ends with the formation of a permanent scar. The discovery of new compounds that act on regeneration can provide information on how to accelerate wound healing, as well as how to improve the cosmetic aspects of healing.
Aging is a complex phenomenon characterized by progressive decline in physiological functions often accompanied by many pathological diseases. It is known that the loss of elasticity in the skin associated with chronological aging and wrinkling is associated with the increase of senescent fibroblasts. Fibroblasts have numerous functions, including cell-cell communication and signaling with other fibroblasts and endothelial cells, and the synthesis and deposition of extracellular matrix, the primary constituent in the structural assembly of the dermis, the deep layer of the skin. These cell-cell contacts affect electrophysiological properties, the secretion of growth factors and cytokines, and enhancement of blood vessel formation. Thus, fibroblasts play a critical role for maintaining the proper function of tissues as well as remodeling.
Senescent fibroblasts lose the ability to synthesize proteins, especially collagen, which is a major component of the extracellular matrix. Molecules of the extracellular matrix (ECM) promote cell adhesion, activate intracellular signaling pathways and modulate the activities of various growth factors and proteins. The loss of collagen occurs in chronological aging and from exposure to extrinsic factors such as ultraviolet radiation or tobacco smoke. Age-related changes observed in fibroblasts include changes in cell morphology and metabolism, decreased proliferative potential, loss of responsiveness to growth factors, decreased production of extracellular matrix proteins such as collagen type I and III, and over-expression of proteases involved in the degradation of extracellular matrix. These modifications tend to decrease the ability of the adaptive response and wound healing, and therefore increase the susceptibility to disease and death.
To ensure normal growth and cell proliferation, it is essential for cells to coordinate the signals arising from nutrients and growth factors as well as inhibitory signals resulting from stress or intracellular signaling. In fact, the interrelationship between cell death, cell survival and cell cycle has become the subject of intense research in recent years.
Apoptosis is a type of programmed cell death that occurs individually, not affecting neighboring structures. The control of cell death is a result of the balance between the expression of anti- and pro-apoptotic proteins in several cell types. Much evidence suggests that mitochondria are the main organelles involved in the processes of cell signaling and death. The mitochondria-dependent intrinsic apoptosis pathway is activated by several stimuli, including damage to DNA, decreased levels of growth factors, heat shock, ultraviolet radiation, gamma radiation, and chemotherapy drugs. DNA damage, especially of mitochondrial DNA, has an important impact on the process of aging.
Among the responses and cellular components involved in mitochondria-dependent intrinsic apoptosis are the production of reactive oxygen species (ROS), loss of cytoplasmic membrane integrity, changes in mitochondrial membrane potential, release of calcium by mitochondria and endoplasmic reticulum, expression and activation of protein caspases and activation of anti- or pro-apoptotic molecules or activation of mitogens. The signaling pathways activated by those agents culminate in the mitochondrial outer membrane permeabilization and the release of soluble apoptotic proteins from the mitochondria intermembrane space. When apoptosis is activated, cytochrome c is released from the mitochondria intermembrane space and can be used as a marker of apoptosis. Pro-apoptotic proteins such as Bax and Bak stimulate the release of this protein, however anti-apoptotic proteins such as Bcl-2 and Bcl-XL inhibit its release. The cytochrome c promotes the activation of pro-caspase 9 to caspase-9, which in turn activates other caspases, culminating in cell death by apoptosis. Activated caspases target specific proteins that maintain the cell structure, leading to cytoskeletal disruption and, consequently, loss of cellular integrity.
The mitochondrion is the major source of intracellular reactive oxygen species (ROS), which play a fundamental role in cellular signaling pathways, mainly in cell proliferation and apoptosis. The interaction of macromolecules with various ROS can impair the function of these organelles and directly influence cell viability and culminate in cell death. Therefore, mitochondria may also be the primary target for the damaging effects of ROS. Some theories speculate that cumulative damage to mitochondria and mitochondrial DNA (mtDNA) caused by ROS is one of the causes of aging. Moreover, extracellular matrix (ECM) components of the basement membrane are not efficiently produced or are degraded by metalloproteinases, causing the loss of cell-matrix adhesion and contributing to cell death by apoptosis.
Because of this, there is an estimated global economic impact of increasing the costs of treating patients with degenerative problems. The search for new compounds or compositions capable of stimulating cell survival, proliferation and activity of fibroblasts is of great interest in the pharmaceutical field for cosmetic treatment and/or prevention of pathologies associated with aging and loss of extracellular matrix.